DESCRIPTION (Applicant?s abstract): The long-term goal of our research is to contribute to developing a treatment for autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common inherited disorders in humans, affecting approximately 500,000 people in the United States alone. ADPKD is characterized by the growth of large cysts on both kidneys. Complications of ADPKD often require long-term treatment for hypertension and renal failure. Two genes are directly linked to ADPKD: PKD1 and PKD2. It is known that pathogenic mutations in these genes result in the loss of protein function. However, the mechanistic link between the loss of PKD2 (or PKD 1) protein function and cyst formation is not known. PKD2 is an integral membrane glycoprotein with structural similarity to cation channels and expressed exclusively in the endoplasmic reticulum (ER) of cultured cells. We have created a series of PKD2 constructs that allow partial expression of polycystin-2 at the plasma membrane. We have begun to use whole-cell patch clamp recording techniques to demonstrate that these constructs express PKD2 on the cell surface and retain a calcium permeable cation current. The experiments outlined in this proposal are designed to build upon this discovery and characterize the unique ion current, pharmacology, and regulation of PKD2 in cells expressing the protein. This information is crucial for elucidating the biological function of PKD2 in intact cells and determining link between the loss of PKD2 protein function and cyst formation in this important human disease.